Our laboratory focuses on understanding how cellular heterogeneity contributes to the pathogenesis of human liver
diseases using cholangiocyte biology as a platform. Cholangiocytes (biliary cells) comprise a highly dynamic
population of cells with morphologically and functionally distinct subtypes that arise from different developmental
origins. Similarly, cholangiopathies refer to a diverse group of disorders that impair biliary cellular homeostasis with
varying etiologies and pathology. Using a novel selective biliary injury model and integrated genetic and
pharmacological approaches in complementary in vivo and in vitro systems, we are elucidating the pathogenesis of
human biliary diseases with emphases on deciphering mechanisms conferring functional heterogeneity of
cholangiocytes in injury responses and how disruption of these processes can drive a biliary phenotype. We also aim to deconstruct gene-environment interactions underlying biliary diseases with the ultimate goal of conceiving and testing novel therapeutic strategies.
OUTBREAKS OF BILIARY ATRESIA
Biliary atresia is an extrahepatic neonatal cholangiopathy that is the most common cause of chronic liver disease in children. Epidemics of biliary atresia had occurred in newborn livestock in Australia in setting of maternal ingestion of the Dysphania plant species during pregnancy.
IDENTIFICATION OF BILIATRESONE
We used an in vivo biliary secretion assay in zebrafish larvae to isolate biliatresone, a previously unknown electrophilic isoflavone, from Dysphania that is responsible for the biliary atresia outbreaks in newborn livestock.
SELECTIVE TOXICITY OF BILIATRESONE
Despite its reactive nature, biliatresone is selectively toxic to the extrahepatic biliary system in the zebrafish as evidenced by the selective destruction of the gallbladder (arrow).